How did Vioxx debacle happen?

As drugmakers scramble to grab Vioxx's multi-billion-dollar share of the
arthritis and pain-relief market, patients might find themselves wondering
whether the competing medications are much safer.

Dr.
Eric Topol of the Cleveland Clinic is critical of how the FDA
handled Merck and Vioxx.

By Tony Dejak,
AP

The fact that no one can answer that question
conclusively, and the fact that Vioxx remained on the market as long as it
did, point to serious deficiencies in how the Food and Drug Administration
regulates prescription drugs, critics say.

Merck yanked Vioxx on Sept. 30 because a new study
had found a higher rate of heart attacks and strokes in patients taking the
drug than in those on a placebo. The move was a stunning denouement for a
blockbuster drug that had been marketed in more than 80 countries with
worldwide sales totaling $2.5 billion in 2003. Vioxx, hawked by the likes
of Olympic gold medalists Dorothy Hamill and Bruce Jenner, had been sold in
the USA for more than five years.

But the new Vioxx study was not the first to raise
concerns about heart attack and stroke risk. "We have been concerned
and aware of the potential for cardiovascular effects for the last few
years," Steven Galson, acting director of the FDA's Center for Drug
Evaluation and Research, said the day Merck announced the withdrawal.
"This is not a total surprise."

In fact, in April 2000 the FDA required Merck to add
labeling information about a possible link to such problems. Yet 2 million
Americans were taking Vioxx when it was pulled.

Critics describe the rise and fall of Vioxx as a
cautionary tale of masterful public relations, aggressive marketing and
ineffective regulation. "The FDA didn't do anything," says Eric
Topol, chief of cardiovascular medicine at the Cleveland Clinic. "They
were passive here."

Sen. Chuck Grassley, R-Iowa, says the FDA was worse
than passive. Investigators for the Senate Finance Committee, which
Grassley chairs, met Thursday with FDA researcher David Graham, lead
scientist on a study presented in August at a medical meeting in France.

Vioxx
timeline

May 1999:
FDA approves Vioxx.

March 2000: Merck reveals that a new
study found Vioxx patients had double the
rate of serious cardiovascular problems than
those on naproxen, an older nonsteroidal
anti-inflammatory drug, or NSAID.

November 2000:The New
England Journal of Medicine publishes
the study, called VIGOR.

February 2001: An advisory panel
recommends the FDA require a label warning
of the possible link to cardiovascular
problems.

September 2001: The FDA warns Merck
to stop misleading doctors about Vioxx's
effect on the cardiovascular system.

April 2002: The FDA tells Merck to
add information about cardiovascular risk to
Vioxx's label.

Aug. 25, 2004: An FDA researcher
presents results of a database analysis of
1.4 million patients; it concludes that
Vioxx users are more likely to suffer a
heart attack or sudden cardiac death than
those taking Celebrex or an older NSAID.

Sept. 23, 2004: Merck says it learned
this day that patients taking Vioxx in a
study were twice as likely to suffer a heart
attack or stroke as those on placebo.

Sept. 30, 2004: Merck withdraws Vioxx
from the U.S. and the more than 80 other
countries in which it was marketed.

The study, an analysis of a database of 1.4 million
Kaiser Permanente members, found that those who took Vioxx were more likely
to suffer a heart attack or sudden cardiac death than those who took
Celebrex, Vioxx's main rival. Based on their findings, Graham and his
collaborators linked Vioxx to more than 27,000 heart attacks or sudden
cardiac deaths nationwide from the time it came on the market in 1999
through 2003.

Graham told the finance committee investigators that
the FDA was trying to block publication of his findings, Grassley said in a
statement. "Dr. Graham described an environment where he was
'ostracized,' 'subjected to veiled threats' and 'intimidation,' "
Grassley said. Graham gave Grassley copies of e-mail that appear to support
his claims that his superiors suggested watering down his conclusions.

Rep. Tom Davis, R-Va., chair of the House Government
Reform Committee, last week wrote acting FDA commissioner Lester Crawford
to ask what the agency knew about Vioxx and when. Davis also asked whether
the FDA plans to collect more data on related drugs.

"In light of Merck's withdrawal of Vioxx ...
and other recent news stories examining FDA's review of the safety and
efficacy of antidepressant drug use by children, I am concerned whether FDA
has been sufficiently aggressive in monitoring drug safety," Davis
wrote.

Topol, in a column posted last week on The New
England Journal of Medicine's Web site, called for a congressional
review of the Vioxx "catastrophe." "The senior executives at
Merck and the leadership at the FDA share responsibility for not having
taken appropriate action and not recognizing that they are accountable for
the public health."

So far, Vioxx is the only drug in its class linked
to a significant increase in heart attacks and strokes. But the European
Agency for the Evaluation of Medicinal Products last week announced it will
review all long-term cardiovascular safety data for Vioxx and the four
other related drugs licensed in Europe.

"It is important to note that the results of
clinical studies with one drug in a given class are not necessarily
applicable to others in a class," Peter Kim, president of Merck
Research Laboratories, was quick to say at a news conference announcing
Vioxx's withdrawal.

Merck happens to have a Vioxx classmate called
Arcoxia in the wings. It is sold in 47 countries but not yet in the USA.
The company expects to hear about its application to the FDA by month's
end, spokesman Christopher Loder says.

Digesting NSAIDs

Like ibuprofen and naproxen, Vioxx is a
non-steroidal anti-inflammatory drug, or NSAID. But Vioxx belongs to a
fairly new class of NSAIDs called COX-2 inhibitors. With Vioxx's demise,
Pfizer's Celebrex and Bextra are the only COX-2 inhibitors sold in U.S.
markets.

No one has ever said that COX-2 inhibitors are more
effective than classic NSAIDs. Their selling point always has been that
they're less likely to cause bleeding and other digestive tract
complications

Although FDA approved the COX-2 inhibitors, it
wasn't convinced they were safer. The drugs had to carry the same digestive
warning as classic NSAIDs. So Merck and Pharmacia, which later merged with
Pfizer, launched studies to prove their drugs shouldn't be lumped with
other NSAIDs.

The Celebrex trial failed to convince the FDA that
the drug was safer, but it didn't appear to be riskier, either. Merck's
trial backfired. Though the study did demonstrate that Vioxx was safer on
the digestive tract than naproxen, it also unexpectedly found that the
COX-2 inhibitor doubled the risk of cardiovascular problems.

In a written response to Topol's New England
Journal of Medicine column, Merck said it "promptly disclosed
these results to the FDA, the scientific community and the media beginning
in March 2000."

But from the start, Merck put a positive spin on the
data. A press release on March 27, 2000, led off with the finding that
Vioxx caused fewer digestive tract problems than naproxen. It did go on to
say that "significantly fewer thromboembolic events (in other words,
heart attacks and strokes) were observed in patients taking naproxen."

However, it wasn't that Vioxx caused cardiovascular
problems, but that naproxen protected against them, Merck argued for the
next 4½ years. Yet, Merck acknowledged in the March 2000 press release,
"this effect ... had not been observed previously in any clinical
studies for naproxen."

Worrisome findings

In February 2001, Merck tried to convince an FDA
advisory committee that Vioxx be allowed to drop the digestive tract
warning. But the committee couldn't ignore the cardiovascular findings.

Still, Merck's marketing machine churned on. In
September 2001, the FDA ordered the company to send doctors a letter
"to correct false or misleading impressions and information"
about Vioxx's effect on the cardiovascular system.

In April 2002, the FDA followed its advisory panel's
recommendation and required that Merck note a possible link to heart
attacks and strokes on Vioxx's label.

"Meanwhile," Topol writes in The New
England Journal of Medicine, "Merck was spending more than $100
million a year in direct-to-consumer advertising — another activity
regulated by the FDA and a critical mechanism in building the 'blockbuster'
status of a drug."

Direct-to-consumer advertising was meant to heighten
awareness of drugs, not to hype them, says pharmacologist Raymond Woosley,
vice president for health sciences at the University of Arizona. "Do
we need to be told how much greater one drug is than the other?"
Woosley asks. "The public can't understand the subtle
differences."

Merck continued to minimize unfavorable findings up
to a month before withdrawing Vioxx. On Aug. 26, the company fired off a
press release refuting Graham's study. "Merck stands behind the
efficacy, overall safety and cardiovascular safety of Vioxx," it said.

Only randomized, controlled trials, in which
patients are randomly assigned to treatment groups (the type of study that
first raised heart concerns back in 2000) can provide unimpeachable data
about a drug's safety and effectiveness, the release pointed out.

Finally, late last month, Merck confronted
unfavorable findings that it could not explain away. Merck had sponsored a
three-year, 2,600-patient randomized trial to see whether Vioxx, like
Celebrex, could claim that it protects against the recurrence of colon
polyps, which can become cancerous.

Again, the study backfired. After 18 months of
treatment, researchers observed a higher heart attack and stroke risk in
patients on Vioxx, Merck says. The drug was compared with a placebo and not
another NSAID, so Merck could not divert blame away from Vioxx. Merck has
not yet reported the study results, but the FDA says 3.5% of the subjects
on Vioxx had suffered a heart attack or stroke, compared with 1.9% on
placebo.

Monitoring the drugs

FDA spokeswoman Crystal Rice says the agency will
continue to monitor drugs in the same class as Vioxx. Besides Merck's
Arcoxia, the FDA is considering whether to approve Novartis' Prexige.
Pfizer is expected to resubmit an application for parecoxib by year's end.
The FDA turned down its original application in 2001 for lack of data.

Since becoming aware of the Vioxx study's finding,
Rice says, the FDA is "much more sensitized to the possibility of
seeing this adverse event" in related drugs.

Sometimes, a drug triggers such an unusual problem
that it's fairly easy to connect the dots, Wood says. "But there was
no possibility that you could discern a heart attack due to Vioxx from a
heart attack not due to Vioxx," he says.

Wood, Topol and others speculate that drugs in the
same class as Vioxx may appear to be safe because the FDA has not yet asked
for the randomized, controlled trials necessary for definitive answers.

"The spotlight is now on Pfizer and the
FDA," says Garret FitzGerald, chair of pharmacology at the University
of Pennsylvania. "The agency needs to scrutinize all ongoing trials in
the light of these data and to decide swiftly" if all COX-2 inhibitors
should carry a warning about heart attacks and strokes.

Topol says the drugs should be specifically tested
in patients known to have cardiovascular disease, which is common in
patients who need medication for osteoarthritis. So far, such patients have
virtually been excluded from trials of the COX-2 inhibitors, Topol says.

In a yearlong study of more than 18,000
osteoarthritis patients published in August, Prexige did not increase heart
attack or stroke risk when compared with ibuprofen or naproxen. However,
Topol wrote in an accompanying editorial, fewer than 2% of study
participants had had a heart attack or undergone bypass surgery or
angioplasty before enrolling.

Back in 2000, when Merck first notified the FDA that
Vioxx appeared to carry a higher risk of heart attacks and strokes than
naproxen, the agency should have quickly ordered a trial comparing Vioxx
with a placebo, Wood says. In the end, he notes, "a relatively small
study was all that it took to show this problem."

Meanwhile, patients try not to worry.

Marjorie Chepp of Milwaukee had been taking Vioxx
for nearly two years. Her doctor first prescribed it for a knee injury, but
Chepp found that it also relieved her osteoarthritis and fibromyalgia. She
asked to remain on it.

"For years I had refused to take meds other
than over-the-counter because I was always afraid of the long-term
effects," says Chepp, 47, an exercise instructor who had an ulcer at
16. "Of course, what happens with the first one I take? It gets
recalled."